As-CATH1–6, novel cathelicidins with potent antimicrobial and immunomodulatory properties from Alligator sinensis, play pivotal roles in host antimicrobial immune responses

Author:

Chen Yan1,Cai Shasha2,Qiao Xue2,Wu Mali3,Guo Zhilai4,Wang Renping5,Kuang Yi-Qun6,Yu Haining2,Wang Yipeng1

Affiliation:

1. Department of Pharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China

2. Department of Bioscience and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116023, China

3. Guizhou Province Center of Disease Control and Protection, Guiyang, Guizhou 550004, China

4. Biology Department, Guizhou Normal University, Guiyang, Guizhou 550000, China

5. Anhui Chinese Alligator National Nature Reserve, Xuancheng, Anhui 242034, China

6. Center for Translational Medicine, Huaihe Clinical College, Huaihe Hospital of Henan University, Kaifeng, Henan 475000, China

Abstract

Crocodilians are regarded as possessing a powerful immune system. However, the composition and action of the crocodilian immune system have remained unclear until now. Cathelicidins, the principal family of host defense peptides, play pivotal roles in vertebrate immune defense against microbial invasions. However, cathelicidins from crocodilians have not been extensively studied to date. In the present study, six novel cathelicidins (As-CATH1–6) were identified and characterized from the endangered Chinese alligator (Alligator sinensis). As-CATH1–6 exhibit no sequence similarity with any of the known cathelicidins. Structure analysis indicated that As-CATH1–3 adopt a random coil secondary conformation, whereas As-CATH4–6 were predicted to mainly adopt an amphipathic α-helix conformation. Among them, As-CATH4–6 exhibited potent, broad-spectrum and rapid antimicrobial activity by inducing the disruption of cell membrane integrity. They also exhibited strong ability to prevent the formation of bacterial biofilms and eradicate preformed biofilms. Furthermore, As-CATH4–6 exhibited potent anti-inflammatory activity by inhibiting the lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and pro-inflammatory cytokines in mouse peritoneal macrophages. They directly neutralized LPS toxicity and therefore inhibited the binding of LPS to the TLR4 receptor and the subsequent activation of inflammatory response pathways. In a peritonitis mice model, As-CATH2–6 provided effective protection against bacterial infection through enhanced immune cell recruitment. In the host Chinese alligator, As-CATH1–6 are mainly expressed in immune organs and epithelial tissues. Bacterial infection significantly enhances their expression, which implies an important role in host anti-infective response. Taken together, the diversity and multiple functions of As-CATH1–6 partially reveal the powerful immune system of the Chinese alligator.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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